Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000277.1:c.1171_1172del

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CA16020956

553594 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f10c8ee8-5a9e-49ac-82f1-d14021ad1340

Approved on: 2020-06-19

Published on: 2020-06-19

HGVS expressions

NM_000277.1:c.1171_1172del

NM_000277.2:c.1171_1172del

NM_001354304.1:c.1171_1172del

NM_000277.3:c.1171_1172del

NM_001354304.2:c.1171_1172del

ENST00000307000.7:c.1156_1157del

ENST00000549247.6:n.930_931del

ENST00000551114.2:n.833_834del

ENST00000553106.5:c.1171_1172del

ENST00000635477.1:n.275_276del

ENST00000635528.1:n.686_687del

NC_000012.12:g.102843677_102843678del

CM000674.2:g.102843677_102843678del

NC_000012.11:g.103237455_103237456del

CM000674.1:g.103237455_103237456del

NC_000012.10:g.101761585_101761586del

NG_008690.1:g.78929_78930del

NG_008690.2:g.119737_119738del

Pathogenic

PP4_Moderate PM3 PM2 PVS1

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1171_1172del (p.Ser391PhefsTer2) variant in PAH has been reported in an individual with Classic PKU (BH4 deficiency excluded). (PMID: 8268925, 11708866, 27121329) in trans with pathogenic variant p.Ser349Pro. It is a frameshift variant in exon 11 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. This variant has an extremely low allele frequency (MAF=0.000008799) in gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate,

PP4_Moderate

Seen in an individual with Classic PKU. PMID: 8268925, PMID: 11708866 A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity. PMID: 27121329

Seen in individual with Classic PKU. PubMed:8268925

Seen in an individual with Classic PKU. PubMed:11708866

PM3

detected in trans with p.[Ser349Pro] (P/LP). Segregation analysis was done to rule out the presence of large genomic rearrangements. PMID: 27121329

PubMed:27121329

PM2

Absent from controls in ExAC, 1000 Genomes, and ESP. MAF=0.000008799 in gnomAD

PVS1

frameshift variant in exon 11 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function

Curation History

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